title: SNAI1-mediated epithelial-mesenchymal transition confers chemoresistance and cellular plasticity by regulating genes involved in cell death and stem cell maintenance.
abstract: Tumor cells at the tumor margin lose epithelial properties and acquire features of mesenchymal cells, a process called epithelial-to-mesenchymal transition (EMT). Recently, features of EMT were shown to be linked to cells with tumor-founding capability, so-called cancer stem cells (CSCs). Inducers of the EMT include several transcription factors, such as Snail (SNAI1) and Slug (SNAI2), as well as the secreted transforming growth factor (TGFß). In the present study, we found that EMT induction in MCF10A cells by stably expressing SNAI1 contributed to drug resistance and acquisition of stem/progenitor-like character as shown by increased cell population for surface marker CD44(+)/CD24(-) and mammosphere forming capacity. Using a microarray approach, we demonstrate that SNAI1 overexpression results in a dramatic change in signaling pathways involved in the regulation of cell death and stem cell maintenance. We showed that NF-κB/MAPK signaling pathways are highly activated in MCF10A-SNAI1 cells by IL1ß stimulation, leading to the robust induction in IL6 and IL8. Furthermore, MCF10A-SNAI1 cells showed enhanced TCF/ß-catenin activity responding to the exogenous Wnt3a treatment. However, EMT-induced stem/progenitor cell activation process is tightly regulated in non-transformed MCF10A cells, as WNT5A and TGFB2 are strongly upregulated in MCF10A-SNAI1 cells antagonizing canonical Wnt pathway. In summary, our data provide new molecular findings how EMT contributes to the enhanced chemoresistance and the acquisition of stem/progenitor-like character by regulating signaling pathways.
authors.affiliation: Institute of Pathology, University of Cologne, Cologne, Germany.
authors.forename: Soyoung
authors.initials: S
authors.lastname: Lim
authors.forename: Astrid
authors.initials: A
authors.lastname: Becker
authors.forename: Andreas
authors.initials: A
authors.lastname: Zimmer
authors.forename: Jianrong
authors.initials: J
authors.lastname: Lu
authors.forename: Reinhard
authors.initials: R
authors.lastname: Buettner
authors.forename: Jutta
authors.initials: J
authors.lastname: Kirfel
mesh_terms: D016923:Cell Death / Q000502:physiology*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000096:biosynthesis; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology; D014411:Neoplastic Stem Cells / Q000473:pathology*; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; C000604407:SNAI1 protein, human; C000604408:SNAI2 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors